Early onset type 2 diabetes mellitus: an update.

The incidence and prevalence of type 2 diabetes mellitus (T2DM) in young individuals (aged <40 years) have significantly increased in recent years, approximating two to threefold increase in the respective rates. Numerous risk factors including severe obesity, family history, ethnicity, maternal diabetes or gestational diabetes, and female sex contribute to a younger age of onset. In terms of pathogenesis, impaired insulin secretion is the key operating mechanism, alongside with ectopic adiposity-related insulin resistance. T2DM diagnosis in a young adult requires the exclusion of type 1 diabetes mellitus (T1DM), latent autoimmune diabetes of adults (LADA) and maturity-onset diabetes of the young (MODY). The establishment of such diagnosis is critical for prognosis, because early-onset T2DM is associated with rapid deterioration in pancreatic ß-cell secretory function leading to earlier initiation of insulin therapy. Furthermore, mortality and lifetime risk of developing complications, especially microvascular, is increased in these patients compared to both later-onset T2DM and T1DM patients; also, the latter are often developed earlier in the course of disease. The management of early-onset T2DM follows the same guidelines as in later-onset T2DM; yet patients aged 18-39 years are underrepresented in the big clinical trials on which the development of guidelines is based. Finally, young people with T2DM face significant challenges associated with social determinants, which compromise their adherence to therapy and induce diabetes distress. Future research focusing on the pathogenesis of ß-cell decline and complications, as well as on specific treatment shall lead to better understanding and management of early-onset T2DM.

Cardiac disease in Cushing's syndrome. Emphasis on the role of cardiovascular magnetic resonance imaging.

BACKGROUND: Cushing's Syndrome (CS) is associated with increased cardiovascular morbidity and mortality. In endogenous CS, cardiovascular mortality remains increased for up to 15 years post remission of hypercortisolism. Similarly, patients with exogenous CS have 4-fold increased incidence of cardiovascular events, regardless of pre-existing cardiovascular disease (CVD). OBJECTIVE: To present the pathophysiology, prognosis, clinical and imaging phenotype of cardiac disease in CS. METHODS: A Pubmed search for cardiac disease in CS over the last 20 years was conducted using combinations of relevant terms. Preclinical and clinical studies, as well as review papers reporting on subclinical heart failure (HF), cardiomyopathy, coronary heart disease (CHD), and cardiovascular imaging were selected. RESULTS: Cardiac disease in CS is associated with direct mineralocorticoid and glucocorticoid receptor activation, increased responsiveness to angiotensin II, ectopic epicardial adiposity, arterial stiffness and endothelial dysfunction, as well as with diabetes mellitus, hypertension, hyperlipidemia, obesity and prothrombotic diathesis. Subclinical HF and cardiomyopathy are principally related to direct glucocorticoid (GC) effects and markedly improve or regress post hypercortisolism remission. In contrast, CHD is related to both direct GC effects and CS comorbidities and persists post cure. In patients without clinical evidence of CVD, echocardiography and cardiac magnetic resonance (CMR) imaging reveal left ventricular hypertrophy, fibrosis, diastolic and systolic dysfunction, with the latter being underestimated by echocardiography. Finally, coronary microvascular disease is encountered in one third of cases. CONCLUSION: Cardiovascular imaging is crucial in evaluation of cardiac involvement in CS. CMR superiority in terms of reproducibility, operator independency, unrestricted field of view and capability of tissue characterisation makes this modality ideal for future studies.

Secondary diabetes mellitus in pheochromocytomas and paragangliomas.

Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.

Biological therapies for premature ovarian insufficiency: what is the evidence?

Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies.

Secondary diabetes mellitus in acromegaly.

Secondary diabetes mellitus (DM) is a common complication of acromegaly, encountered in up to 55% of cases. Vice versa, the prevalence of acromegaly is markedly higher in cohorts of patients with type 2 DM (T2DM). The presence of secondary DM depends primarily on acromegaly status and is associated with increased cardiovascular morbidity, malignancy rate and overall mortality. The principal pathophysiologic mechanism is increased insulin resistance due to excessive lipolysis and altered fat distribution, reflected at the presence of intermuscular fat and attenuated, dysfunctional adipose tissue. Insulin resistance is ascribed to the direct, diabetogenic effects of growth hormone (GH), which prevail over the insulin-sensitizing effects of insulin-like growth factor 1 (IGF-1), probably due to higher glucometabolic potency of GH, IGF-1 resistance, or both. Inversely, GH and IGF-1 act synergistically in increasing insulin secretion. Hyperinsulinemia in portal vein leads to enhanced responsiveness of liver GH receptors and IGF-1 production, pointing towards a mutually amplifying loop between GH-IGF-1 axis and insulin. Secondary DM occurs upon beta cell exhaustion, principally due to gluco-lipo-toxicity. Somatostatin analogues inhibit insulin secretion; especially pasireotide (PASI) impairs glycaemic profile in up to 75% of cases, establishing a separate pathophysiologic entity, PASI-induced DM. In contrast, pegvisomant and dopamine agonizts improve insulin sensitivity. In turn, metformin, pioglitazone and sodium-glucose transporters 2 inhibitors might be disease-modifying by counteracting hyperinsulinemia or acting pleiotropically. Large, prospective cohort studies are needed to validate the above notions and define optimal DM management in acromegaly.

Secondary diabetes mellitus due to primary aldosteronism.

Primary aldosteronism (PA) and diabetes mellitus (DM) are clinical conditions that increase cardiovascular risk. Approximately one in five patients with PA have DM. Nevertheless, the pathophysiology linking these two entities is not entirely understood. In addition, the majority of patients with PA have glucocorticoid co-secretion, which is associated with increased risk of impaired glucose homeostasis. In the present review, we aim to comprehensively discuss all the available research data concerning the interplay between mineralocorticoid excess and glucose metabolism, with separate analysis of the sequalae in muscle, adipose tissue, liver and pancreas. Aldosterone binds both mineralocorticoid and glucocorticoid receptors and amplifies tissue glucocorticoid activity, via 11-ß-hydroxysteroid dehydrogenase type 1 stimulation. A clear classification of the molecular events as per specific receptor in insulin-sensitive tissues is impossible, while their synergistic interaction is plausible. Furthermore, aldosterone induces oxidative stress and inflammation, perturbs adipokine expression, thermogenesis and lipogenesis in adipose tissue, and increases hepatic steatosis. In pancreas, enhanced oxidative stress and inflammation of beta cells, predominantly upon glucocorticoid receptor activation, impair insulin secretion. No causality between hypokalemia and impaired insulin response is yet proven; in contrast, hypokalemia appears to be implicated with insulin resistance and hepatic steatosis. The superior efficacy of adrenalectomy in ameliorating glucose metabolism vs. mineralocorticoid receptor antagonists in clinical studies highlights the contribution of non-mineralocorticoid receptor-mediated mechanisms in the pathophysiologic process. The exact role of hypokalemia, the mechanisms linking mineralocorticoid excess with hepatic steatosis, and possible disease-modifying role of pioglitazone warrant further studies.